synaptic transmission and neuronal excitability can be reversed by CB1 or 5HT1A
receptor antagonists (Ledgerwood et al. 2011 ). Micromolar concentrations of CBD
decrease postsynaptic membrane resistance and spikefiring of CA1 pyramidal
neurons stimulated by current injection, and increase the minimum stimulus
required to evoke spiking. With the exception of the decreased membrane resis-
tance, the effects of CBD were retained in the presence of the CB1 antagonist
SR141716A. However, when SR141716A was tested alone, the steady-state
membrane resistance increased, an endogenous effect opposite in direction from
that caused by CBD alone, which may account for the apparent loss of this CBD
effect (Ledgerwood et al. 2011 ). These results were are consistent with CBD actions
on Na+channels, but it was also noted that the relationship between CBD’s effects
on Na+channels and anticonvulsant effects remains to befirmly established (Hill
et al. 2014 ; Patel et al. 2016 ). For example, mutations in the SCN8A gene for
voltage-gated sodium channel (VGSC) Nav1.6 have been found in patients with
severe early infantile epileptic encephalopathy, and mutations in the SCN1A gene
encoding the VGSC Nav1.1 have been associated with generalized epilepsy with
febrile seizures and Dravet syndrome. Recently, it was shown that CBD prefer-
entially attenuates resurgent sodium currents over peak transient currents generated
by wild-type Nav1.6 as well as the aberrant resurgent and persistent current gen-
erated by Nav1.6 mutant channels in transfected cells and striatal neurons.
Moreover, CBD reduces the overall action potentialfiring of striatal neurons. This
suggests that CBD could also be attenuating neuronal excitability and excitotoxi-
city, at least in part, through its actions on voltage-gated Na+channels and aberrant
resurgent current. (Patel et al. 2016 ).
G protein-coupled receptor 55 (GPR55) is also sensitive to certain cannabinoids.
It is widely distributed in the central nervous system (Ryberg et al. 2007 ), and
activation by agonists triggers mobilization of intracellular Ca2+in neuronal cell
cultures and hippocampal slices, where it leads to repetitive release of the excitatory
neurotransmitter glutamate (Sylantyev et al. 2013 ). Interestingly, these effects in
hippocampal slices were abolished by CBD acting as a GPR55 antagonist or
through deletion of GPR55 in knockout mice. CBD also activates and desensitizes
TRP cation channels, specifically TRPV1, TRPV2 and TRPA1 (Iannotti et al.
2014 ). Thus, further investigation of the actions of CBD on TRP ion channels in
in vitro and in vivo models of kindling, seizures and epilepsy appears warranted.
Molecular targets beyond cannabinoid receptors and ion channels involved in
neuronal excitability are also modulated by CBD in vitro (e.g., see Beique et al.
2004 ; Fernández-Ruiz et al. 2013 ; Stiedl et al. 2015 ), and these systems might also
provide therapeutic benefit in epilepsy and its associated comorbidities such as
depression, sleep disorders, anxiety and inflammation. For instance, CBD’s
anti-inflammatory effects through inhibition of equilibrative nucleoside transport,
enhanced endogenous activation of adenosine receptors and inhibition of TNFa
release may also contribute to its therapeutic benefit in epilepsy (During and
Spencer 1992 ; Carrier et al. 2006 ; Martin-Moreno et al. 2011 ; Vezzani et al. 2011 ;
Ribeiro et al. 2012 ). It is also interesting to note an observation made later that
whole plant CBD-rich cannabis“is superior over [purified, synthetic] CBD for the
254 B.F. Thomas